Polymorphism is the ability of a compound to crystallize as more than one distinct crystal species. Different polymorphic forms (or polymorphs) have different arrangements or conformations of the molecules in the crystal lattice. If a solid does not possess a distinguishable crystal lattice and the molecular arrangement of molecules is disordered, it is considered amorphous. The amorphous state is structurally similar to the liquid state [W. McCrone, Phys. Chem. Org. Solid State (1965) 2:725767].
Polymorphic forms of a drug substance can have different chemical, physical and physicotechnical properties. Differences can result from e.g. packing of molecules in the crystal structure (density, refractive index, conductivity, hygroscopicity), thermodynamic properties (melting point, heat capacity, vapor pressure, solubility), kinetic properties (dissolution rate, stability), surface properties (surface free energy, interfacial tension, shape, morphology), and mechanical properties (compactibility, tensile strength). These properties can have a direct effect on the ability to process and manufacture the active pharmaceutical ingredient (API) and the drug product. Polymorphism further has pharmacological implications due to altered solid state properties and suitability for a particular formulation. Thus, polymorphism of an API can affect the quality, safety, efficacy and developability of a drug product and is therefore of fundamental importance [D. Giron et al., J. Therm. Anal. Cal. (2004) 77:709].
In addition to polymorphic modifications, an API can be crystallized in different salt forms with an appropriate counterion. Similar to polymorphism, salt forms are varying from each other in the degree of solubility and many other physical and chemical factors, as denoted above. As compared to the free acid or free base of the API, an appropriate salt form might provide improved aqueous solubility, dissolution rate, hygroscopicity, chemical stability, melting point, or mechanical properties.
Solvates, also known as pseudopolymorphs, are crystal forms having either stoichiometric or nonstoichiometric amounts of a solvent incorporated in the crystal lattice. If the incorporated solvent is water, the solvate is commonly known as a hydrate.
The compound of formula (I), its manufacture, its pharmacological activity as Lysine Specific Demethylase-1 (LSD1) inhibitor, and its use for the treatment, prevention and/or delay of progression of diseases associated with LSD1 have been described in WO 2013/057322 (A1).
The compound of formula (I) has now been found to be a highly potent active pharmaceutical ingredient (HPAPI). HPAPIs are effective at much smaller dosage levels than traditional APIs. HPAPIs on one hand are beneficial since they allow effective medicines that require lower doses and hence provoke fewer side effects, but on the other hand they lead to new manufacturing challenges. Safety, Health and Environment (SHE) requirements in compliance with regulatory guidelines necessitate segregated high-containment manufacturing with complex needs regarding facility design, equipment selection and manufacturing processes to achieve desired levels of containment, minimized operator exposure, and ensured worker protection and safety. Hence the highly potent nature is a major issue for process development and manufacturing.
The compound of formula (I) as obtained according to the description of WO 2013/057322 (A1) results in tiny needle shaped crystalline particles in polymorphic Form A.
The final reaction step of the process for the manufacture of the compound of formula (I) is the deprotection of the compound of formula (BOC-I), the tert-butyloxycarbonyl (BOC) protected compound of formula (I), using hydrochloric acid in a solvent, followed by filtration of the obtained solid. Reactive precipitation upon cleavage of the BOC-protecting group with excess HCl under conditions as described in Example 5 on page 158 of WO 2013/057322 (A1) yields a slurry of extremely small particles of Form A which are hardly filterable from the reaction mixture, because e.g. the filter gets clogged. In addition, the small particles of Form A are easily getting electrostatically charged. Handling of the particles with metal equipment (such as spatula) is hardly possible.
Such solid state and particle shape is strongly unwanted for HPAPIs making it very difficult to manufacture the compound of formula (I) in a safe and well-contained way.
There is thus a need for new improved processes and for new improved polymorphic forms in alternative, better processable crystal habits.
In addition, the deprotection of the BOC group under conditions as described in Example 5 on page 158 of WO 2013/057322 (A1) may yield genotoxic by-products from the reaction of the hydrochloric acid and the solvent, thus requiring additional purification steps.
It is also known in the art, that di-hydrochloric acid salts of APIs are prone to decomposition to mono-hydrochloric acid salts thereby releasing corrosive hydrochloric acid. In the development of APIs it is thus normally undesirable to develop di-hydrochloric acid salts because of their known lack of stability and corrosiveness. Surprisingly, a stable di-hydrochloric acid salt of the compound of formula (I) has been found, which does not decompose and release corrosive hydrochloric acid.
It has now been surprisingly found, that under certain conditions new solid forms of the compound of formula (I) can be obtained, which are described hereinafter, which have advantageous utilities and properties. They exhibit substantially different and superior physical and physicochemical properties which may be beneficial in various aspects relevant in API and drug product development, e.g. for dissolution of API, stability and shelf life of API and drug product, and/or facilitated routes of manufacturing or purification. In particular, the instant invention provides novel solid forms of the compound of formula (I) with improved processability, improved safety as well as increased stability of the API.
The new solid forms as described herein are distinguishable by analytical methods as known in the art, particularly by X-ray powder diffraction, crystal structure analysis, vibrational spectroscopy, magnetic resonance and mass spectroscopy, calorimetry, thermogravimmetry, dynamic vapor sorption as well as by microscopy.
The new process for the manufacture of the new solid forms of the compound of formula (I) does not produce any genotoxic by-products making additional purification steps of the product superfluous. The obtained product is therefore of higher purity and reduced toxicity and is produced in a cheaper more efficient and more ecological way.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, suitable methods and materials are described below.
All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.
The nomenclature used in this Application is based on IUPAC systematic nomenclature, unless indicated otherwise.
Any open valency appearing on a carbon, oxygen, sulfur or nitrogen atom in the structures herein indicates the presence of hydrogen, unless indicated otherwise.
The term “C1-7 alcohol” denotes a linear or branched saturated hydrocarbon molecule of 1 to 7 carbon atoms, wherein at least one of the hydrogen atoms has been replaced by a hydroxy group. In particular embodiments, the alcohol has 1 to 4 carbon atoms. In particular embodiments one of the hydrogen atoms has been replaced by a hydroxy group. Particular examples of C1-7 alcohol include methanol, ethanol, isopropanol or 2-propanol, n-propanol or 1-propanol, n-butanol or 1-butanol, iso-butanol or 2-methylpropan-1-ol, and tert-butanol or 2-methylpropan-2-ol. Most particular example of C1-7 alcohol is 1-propanol.
The term “optional” or “optionally” denotes that a subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
The term “active pharmaceutical ingredient” (or “API”) denotes the compound in a pharmaceutical composition that has a particular biological activity.
The term “pharmaceutically acceptable” denotes an attribute of a material which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and is acceptable for veterinary as well as human pharmaceutical use.
The terms “pharmaceutically acceptable excipient” and “therapeutically inert excipient” can be used interchangeably and denote any pharmaceutically acceptable ingredient in a pharmaceutical composition having no therapeutic activity and being non-toxic to the subject administered, such as disintegrators, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants, carriers, diluents or lubricants used in formulating pharmaceutical products.
The term “pharmaceutical composition” denotes a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient together with pharmaceutically acceptable excipients to be administered to a mammal, e.g., a human in need thereof.
The term “solid form” or “form” is a general term to denote a crystal form and/or amorphous form of a solid material.
The terms “crystal form” and “crystalline form” can be used interchangeably to denote polymorphs and pseudo-polymorphs of a crystalline solid.
The terms “polymorph” and “modification” can be used synonymously to denote one particular crystal structure in which a compound can crystallize. Different polymorphs have different arrangements or conformations of the molecules in the crystal lattice but all share the same elemental composition.
The term “polymorphism” denotes the ability of a compound to form more than one polymorph.
The term “enantiotropy” denotes the relationship between two or more polymorphs of the same substance in which the rank order of thermodynamic stabilities of the polymorphs changes reversibly at a defined temperature.
The term “monotropy” denotes the relationship between two or more crystal forms of the same substance in which the rank order of thermodynamic stabilities of the polymorphs is retained at all temperatures below the melting point. A “metastable” form is a crystal form which does not have the highest rank order of thermodynamic stability.
The terms “solvate” and “pseudo-polymorph” can be used synonymously to denote a crystal having either stoichiometric or nonstoichiometric amounts of a solvent incorporated in the crystal lattice. If the incorporated solvent is water, the solvate formed is a “hydrate”. When the incorporated solvent is alcohol, the solvate formed is an “alcoholate”.
The term “salt” denotes a material which is composed of two components, an acid and a base with a clearly defined stoichiometric ratio of the two salt formers. Salt crystals are formed by ionic bonding interactions with complete transfer of hydrogen ions between acid and base.
The term “crystal shape” denotes the basic body element(s) (polyhedron(s)) of which a single crystal is built up. The crystal shape is described by the Miller indices of the lattice planes of the polyhedron(s).
The term “crystal habit” denotes the crystal morphology and hence the physical appearance of a solid form. Variations of crystal habit are caused by different growth rates of lattice planes.
The term “equivalent spherical diameter” (or ESD) of a non-spherical object, e.g. an irregularly-shaped particle, is the diameter of a sphere of equivalent volume.
The terms “d50 value” and “mass-median diameter” (or MMD) can be used interchangeably and denote the average particle size by mass, i.e. the average equivalent diameter of a particle, which is defined as the diameter where 50% (w) of the particles of the ensemble have a larger equivalent spherical diameter, and the other 50% (w) have a smaller equivalent spherical diameter.
The term “agglomerate” denotes an assemblage of primary particles which are rigidly joined together as by fusion, sintering or growth. Agglomerates cannot be readily dispersed. The term “agglomeration” denotes a process by which primary particles are joined together to form an agglomerate.
The term “aggregate” denotes an assemblage of primary particles which are loosely attached to each other by contact. Aggregates can be readily dispersed. The term “aggregation” denotes a process by which primary particles are attached to each other to form an aggregate.
The term “amorphous form” denotes a solid material which does not possess a distinguishable crystal lattice and the molecular arrangement of molecules lacks a long-range order. In particular, amorphous denotes a material that does not show a sharp Bragg diffraction peak. Bragg's law describes the diffraction of crystalline material with the equation “2d·sin(theta)=n·lambda”, wherein “d” denotes perpendicular distance (in Angstroms) between pairs of adjacent planes in a crystal (“d-spacing”), “theta” denotes the Bragg angle, “lambda” denotes the wavelength and “n” is an integer. When Bragg's law is fulfilled, the reflected beams are in phase and interfere constructively so that Bragg diffraction peaks are observed in the X-ray diffraction pattern. At angles of incidence other than the Bragg angle, reflected beams are out of phase and destructive interference or cancellation occurs. Amorphous material does not satisfy Bragg's law and no sharp Bragg diffraction peaks are observed in the X-ray diffraction pattern. The XRPD pattern of an amorphous material is further characterized by one or more amorphous halos.
The term “XRPD” denotes the analytical method of X-Ray Powder Diffraction. The repeatability of the angular values is in the range of 2Theta ±0.2°, more particularly in the range of 2Theta ±0.1°. The term “approximately” given in combination with an angular value denotes the variance which is in the range of 2Theta ±0.2°, particularly in the range of 2Theta ±0.1°. The relative XRPD peak intensity is dependent upon many factors such as structure factor, temperature factor, crystallinity, polarization factor, multiplicity, and Lorentz factor. Relative intensities may vary considerably from one measurement to another due to preferred orientation effects. According to USP 941 (US Pharmacopoeia, 37th Edition, General Chapter 941), relative intensities between two samples of the same material may vary considerably due to “preferred orientation” effects. Anisotropic materials adopting preferred orientation will lead to anisotropic distribution of properties such as modulus, strength, ductility, toughness, electrical conductivity, thermal expansion, etc., as described e.g. in Kocks U. F. et al. (Texture and Anisotropy: Preferred Orientations in Polycrystals and Their Effect on Materials Properties, Cambridge University Press, 2000). In XRPD but also Raman spectroscopy, preferred orientations cause a change in the intensity distribution. Preferred orientation effects are particularly pronounced with crystalline APIs of relatively large particle size.
The abbreviation “FWHM” denotes the full width at half maximum, which is a width of a peak (e.g. appearing in a spectrum, particularly in an XRPD pattern) at its half height.
The term “sharp Bragg diffraction peak” in connection with X-ray diffraction patterns denotes a peak which is observed if Bragg's law of diffraction is fulfilled. Generally, the FWHM of a sharp Bragg diffraction peak is less than 0.5° 2-theta.
The term “amorphous halo” in connection with X-ray diffraction patterns denotes an approximately bell-shaped diffraction maximum in the X-ray powder diffraction pattern of an amorphous material. The FWHM of an amorphous halo is on principle larger than the FWHM of the peak of crystalline material.
The terms “FTIR” and “IR” denote the analytical method of infrared spectroscopy.
The term “Raman” denotes the analytical method of Raman spectroscopy. The term “approximately” given in combination with Raman shifts denotes the repeatability which is in the range of ±1 cm−1.
The term “confocal Raman microspectroscopy” (CRM) refers to an analytical device wherein a Raman spectrometer is coupled to an optical microscope with the ability to spatially filter the sample volume. CRM allows high magnification visualisation of a sample and Raman analysis of a sample volume with dimensions down to 1 μm and below (Dieing T. et al. (Eds.), Confocal Raman Microscopy, Springer, 2011).
The term “SEM” denotes the analytical method of Scanning Electron Microscopy. Scanning Electron Microscopy is using a highly focused electron beam to scan the surface of the sample to be imaged. When the electrons of this beam interact with the sample, they extract some electrons of inner shell (secondary electrons) of the atoms at the surface of the sample. These emitted electrons are detected by the so-called secondary electron detector. Due to its position looking at an angle of 45 degrees to the sample in comparison to the axis of the exciting electron beam, this allows to generate a shadowing effect. This shadow effect contributes to the very high topographic resolution of the electron microscopy images. Electron microscopy also has the advantage of a large depth of view.
The term “solid state purity” or “purity of solid forms” refers to the quantitative phase analysis in which the degree of crystallinity and the amount of other solid forms is determined and quantified using XRPD according to United States Pharmacopoeia General Chapter <941>.
The term “micronization” denotes a process whereby the particle size of a solid material is diminished to a d50 value of less than 10 μm by the aid of a suitable method, such as milling, bashing or grinding.
The term “ambient conditions” denotes conditions as experienced in a standard laboratory, e.g. atmospheric pressure, air, ambient temperature between 18° C. and 28° C., humidity between 30% rH and 80% rH.
The term “hygroscopicity” describes the ability of a solid material to adsorb moisture. The hygroscopicity of a given API is characterized [European Pharmacopoeia—6th Edition (2008), Chapter 5.11) by the increase in mass when the relative humidity is raised from 0% rH to 90% rH:                non-hygroscopic: weight increase Δm<0.2%;        slightly hygroscopic: weight increase 0.2%≤Δm<2.0%;        hygroscopic: weight increase 2.0%≤Δm<15.0%;        very hygroscopic: weight increase Δm≥15.0%;        a deliquescent: sufficient water is adsorbed to form a liquid.        
The term “highly potent active pharmaceutical ingredient” (HPAPI) denotes an active pharmaceutical ingredients exhibiting a potency defined by either:                a biologically effective dose at or below 150 μg per kg of body weight;        a therapeutic daily dose at or below 10 mg;        an occupational exposure limit (OEL) at or below 10 μg per m3 of air (8 h time-weighted average); or        an acceptable daily exposure (ADE) at or below 100 μg per day (lifetime exposure).        
The term “Acceptable Daily Exposure” (ADE) denotes the dose that is unlikely to cause an adverse health event or undesirable physiological effects if an individual is exposed at or below this dose for the maximum expected duration of use of the drug carrying the contaminant or alternatively for lifetime use.
According to the “heat-of-fusion rule” (or “enthalpy-of-fusion rule”) by Burger/Ramberger (A. Burger and R. Ramberger, Mikrochim. Acta, 1979, 2, 259-271) the more stable polymorph has the higher melting point and the higher heat of fusion in a monotropic system. If the higher melting polymorph of a compound has the lower enthalpy (heat) of fusion the two polymorphs are enantiotropic. If the lower melting polymorph has the lower entropy (heat) of fusion the two polymorphs are likely to be monotropically related. If the difference in melting points is larger than 30° C., this rule should not be considered.
According to the “density rule” by Burger/Ramberger (A. Burger and R. Ramberger, Mikrochim. Acta, 1979, 2, 259-271) the more stable polymorph has the higher density. In particular the rule states that if a polymorph has a lower density than another polymorph at ambient temperature, then it may be assumed that at absolute zero the form with the lower density is not stable.
The term “Form A” as used herein denotes the crystalline anhydrous polymorphic form A of (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine di-hydrochloride.
The term “Form B” as used herein denotes the crystalline anhydrous polymorphic form B of (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine di-hydrochloride.
The term “Form C” as used herein denotes the crystalline anhydrous polymorphic form C of (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine di-hydrochloride.